bedaquiline and Mycobacterium-Infections

The recent discovery of small molecules targeting the cytochrome

Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents; Antitubercular Agents; Cytochrome Reductases; Diarylquinolines; Electron Transport; Electron Transport Complex IV; Gene Deletion; Humans; Inflammation; Mice; Mice, Inbred BALB C; Mitochondrial Proteins; Mycobacterium bovis; Mycobacterium Infections; Mycobacterium tuberculosis; Oxidative Phosphorylation; Oxidoreductases; Oxygen; Plant Proteins; Synthetic Lethal Mutations; THP-1 Cells

Over the last 10 years, Mycobacterium abscessus group strains have emerged as important human pathogens, which are associated with significantly higher fatality rates than any other rapidly growing mycobacteria. These opportunistic pathogens are widespread in the environment and can cause a wide range of clinical diseases, including skin, soft tissue, central nervous system, and disseminated infections; by far, the most difficult to treat is the pulmonary form. Infections with M. abscessus are often multidrug-resistant (MDR) and require prolonged treatment with various regimens and, many times, result in high mortality despite maximal therapy. We report here the evaluation of diverse mouse infection models for their ability to produce a progressive high level of infection with M. abscessus. The nude (nu/nu), SCID (severe combined immunodeficiency), gamma interferon knockout (GKO), and granulocyte-macrophage colony-stimulating factor (GMCSF) knockout mice fulfilled the criteria for an optimal model for compound screening. Thus, we set out to assess the antimycobacterial activity of clarithromycin, clofazimine, bedaquiline, and clofazimine-bedaquiline combinations against M. abscessus-infected GKO and SCID murine infection models. Treatment of GKO and SCID mice with a combination of clofazimine and bedaquiline was the most effective in decreasing the M. abscessus organ burden.

Topics: Animals; Anti-Bacterial Agents; Clarithromycin; Clofazimine; Diarylquinolines; Granulocyte-Macrophage Colony-Stimulating Factor; Mice; Mice, Knockout; Mice, SCID; Microbial Sensitivity Tests; Mycobacterium; Mycobacterium Infections

The prognosis of Mycobacterium abscessus infections is poor due to the lack of effective drug treatment. The objective of this study was to set up an animal model suitable to test antibiotic activity against M. abscessus.. The following mouse strains were evaluated: Swiss, BALB/c, C57BL/6, nude, beige, A/J, and GKO. Antibiotic activity was tested for clarithromycin, amikacin, cefoxitin, tigecycline, and bedaquiline (TMC207). Finally, we evaluated the 3-drug combination clarithromycin, cefoxitin, and amikacin.. Nude and GKO mice fulfilled criteria for the model but only nude mice offered sufficient availability for large therapeutic experiments. Among the 3 drugs usually combined for treatment of M. abscessus infection, cefoxitin was the most active because it improved survival and reduced bacillary loads in spleen whereas clarithromycin and amikacin prevented death but had little impact on bacillary loads. The triple-drug combination was not more active than cefoxitin alone. Tigecycline displayed bactericidal activity whereas bedaquiline was almost inactive.. Nude mice are an adequate model for in vivo chemotherapy studies. Among tested drugs, cefoxitin and tigecycline showed promising in vivo activity against M. abscessus. The best drug combination remains to be determined.

Topics: Animals; Anti-Bacterial Agents; Colony Count, Microbial; Diarylquinolines; Disease Models, Animal; Female; Kidney; Lung; Male; Mice; Mice, Inbred C57BL; Mice, Nude; Microbial Sensitivity Tests; Minocycline; Mycobacterium; Mycobacterium Infections; Spleen; Statistics, Nonparametric; Tigecycline